The present invention is in the field of receptor proteins that are related to the cytokine receptor subfamily, recombinant DNA molecules, and protein production. The present invention specifically provides novel receptor peptides and proteins and nucleic acid molecules encoding such peptide and protein molecules, all of which are useful in the development of human therapeutics and diagnostic compositions and methods.
Many receptor proteins serve as targets for the action of pharmaceutically active compounds. Additionally, many phamaceutical/therapeutic agents act by competing with and/or blocking the binding of the receptor with it""s natural ligand. It is, therefore, important in developing new pharmaceutical compounds to identify receptor proteins that can be put into high-throughput screening formats. The present invention advances the state of the art by providing novel human receptor proteins that can serve as drug targets.
The novel human protein, and encoding gene, provided by the present invention is related to the family of cytokine receptors, particularly the hematopoietic and inflammatory cytokines, and shows the greatest degree of similarity to granulocyte-macrophage colony-stimulating factor 2 receptor, beta chain (GM-CSF2RB); this beta chain is also shared with the interleukin-5 (IL5RB) (Tavernier et al., Cell 66: 1175-1184, 1991) and interleukin-3 receptors (IL3RB) (Kitamura et al., Cell 66: 1165-1174, 1991). Thus, references herein to CSF2RB include GM-CSF2B, IL5RB, and IL3RB.
Mutations in CSF2RB are associated with pulmonary alveolar proteinosis (Dirksen et al., J. Clin. Invest. 100: 2211-2217, 1997) and acute myeloid leukemia (Dirksen et al., Blood 92: 1097-1103, 1998). Mutations in CSF2RB may also lead to cancer (D""Andrea et al., Blood 83: 2802-2808, 1994) and mutations that lead to over-active CSF2RB may cause hematopoietic disorders, neurological disorders, and myeloproliferative disorders such as polycythema vera (D""Andrea et al, J. Clin. Invest. 102: 1951-1960, 1998). Furthermore, CSF2RB-mediated cytokine signaling plays an important role in regulating cell fate decisions and it has been suggested that a key step in lymphoid commitment is down-regulation of the cytokine receptors that modulate myeloid cell development (Kondo et al., Nature 407: 383-386, 2000).
For further information regarding cytokine receptors such as CSF2RB, see Hayashida et al., Proc Natl Acad Sci U S A December 1990;87(24):9655-9; Tu et al., Blood Aug. 1, 2000;96(3):794-9; Herman et al., J Biol Chem Mar. 3, 2000;275(9):6295-301; Sayani et al., Blood Jan. 15, 2000;95(2):461-9; Gorman et al., J. Biol. Chem. 267: 15842-15848, 1992; Jenkins et al, EMBO J. 14: 4276-4287, 1995; Robb et al., Proc. Nat. Acad Sci. 92: 9565-9569, 1995; and Shen et al., Cytogenet. Cell Genet. 61: 175-177, 1992.
Due to their importance in hematopoietic, inflammatory, and neurological disorders, as well as cancer, leukemia, and myeloproliferative disorders, novel human cytokine receptor proteins/genes, such as provided by the present invention, are valuable as potential targets for the development of therapeutics to treat these and other diseases/disorders. Furthermore, SNPs in cytokine receptor genes, such as provided by the present invention, may serve as valuable markers for the diagnosis, prognosis, prevention, and/or treatment of such diseases/disorders.
Using the information provided by the present invention, reagents such as probes/primers for detecting the SNPs or the expression of the protein/gene provided herein may be readily developed and, if desired, incorporated into kit formats such as nucleic acid arrays, primer extension reactions coupled with mass spec detection (for SNP detection), or TaqMan PCR assays (Applied Biosystems, Foster City, Calif.).
Receptor proteins, particularly members of the cytokine receptor subfamily, are a major target for drug action and development. Accordingly, it is valuable to the field of pharmaceutical development to identify and characterize previously unknown members of this subfamily of receptor proteins. The present invention advances the state of the art by providing previously unidentified human receptor proteins that have homology to members of the cytokine receptor subfamily.
The present invention is based in part on the identification of amino acid sequences of human receptor peptides and proteins that are related to the cytokine receptor subfamily, as well as allelic variants and other mammalian orthologs thereof. These unique peptide sequences, and nucleic acid sequences that encode these peptides, can be used as models for the development of human therapeutic targets, aid in the identification of therapeutic proteins, and serve as targets for the development of human therapeutic agents that modulate receptor activity in cells and tissues that express the receptor. Experimental data as provided in FIG. 1 indicates expression in the placenta, marrow, liver/spleen, and in leukocytes.